Severe bile salt export pump deficiency:: 82 different ABCB11 mutations in 109 families
Severe bile salt export pump deficiency:: 82 different ABCB11 mutations in 109 families
复制标题
DOI：
10.1053/j.gastro.2008.01.038
复制
发表时间：
2008-04-01
期刊：
影响因子：
29.4
通讯作者：
Thompson, Richard J.
中科院分区：
文献类型：
--
作者：
Strautnieks, Sandra S.;Byrne, Jane A.;Thompson, Richard J.
背景与目的：严重胆盐输出泵(BSEP)缺乏的患者表现为进行性胆汁淤积性肝病。我们研究了这些患者中ABCB11(编码BSEP)的突变，以及与残留蛋白检测和恶性风险相关的基因类型。方法：采用单链构象多态分析和ABCB11基因测序的方法，对临床诊断为BSEP缺乏症的肝内胆汁淤积症患者进行检测。根据可能的表型严重程度分类的基因类型与BSEP免疫组织化学数据和临床结果相关。结果：在109个家系中发现82个不同的突变(52个新突变)，其中9个无义突变，10个小插入和缺失，15个剪接点突变，3个全基因缺失，45个错义突变。在7个家系中，尽管进行了完整的序列分析，但只发现了一个杂合子突变。32%的突变发生在>；1家族，58%的欧洲家庭(52/89)存在E297G和/或D482G。在免疫组织化学上。分析88例患者，93%的患者BSEP染色异常或缺失。E297G和D482G的表达差异最大，45%(19/42)的患者检测到一些BSEP。肝细胞癌或胆管细胞癌的发生率为15%(19/128)。两个蛋白质截短突变具有特殊的风险；38%(8/21)的此类患者发展为恶性肿瘤，而10%(11/107)的患者可能没有那么严重的基因类型(相对风险，3.7[可信区间，1.7-8.1；P=0.003])。结论：通过这项研究，现已鉴定出>；100个ABCB11突变。在严重疾病中，免疫组织化学可检测到的BSEP通常缺失或显著降低。BSEP缺乏增加了患肝胆恶性肿瘤的风险。密切监测BSEP缺陷患者保留其天然肝脏，特别是那些携带2个零突变的患者，是必不可少的。
Background & Aims: Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. Methods: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. Results: Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in > 1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical. analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). Conclusions: With this study, > 100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential.